The synaptic circuitry of the lateral habenula and behavioral depression. The neural basis of mood disorders is poorly understood. As a consequence, efforts to develop more effective therapies for depression have largely been unsuccessful. Recent studies indicate that neurons in the lateral habenula (LHb) signal disappointment and may play an important role in depression, however the mechanisms by which the LHb contributes to depression are unknown. Here, we will test the central hypothesis that aberrant activity in the synaptic circuitry of the LHb underlies behavioral depression, and that normalization of LHb neuronal activity is integral to the efficacy of anti-depression treatments. The overall goal of this research program is to gain a better understanding of the cellular changes responsible for the pathogenesis of depression. Using animal models of depression, aberrant neuronal activity in the LHb will be assessed and its underlying synaptic mechanisms will be determined. Furthermore, by selectively manipulating the activity of LHb neurons and determining the behavioral outcomes, the causal relationship between aberrant LHb neuronal activity and behavioral depression will be tested. Importantly, this research program will result in the development of methods that allow the modulation of depression-like behavior in animals. A number of complementary methodologies will be used, including behavioral assays, electrophysiology, two-photon imaging, in vivo circuit tracing, electrical deep brain stimulation, molecular genetics, and optogenetic techniques. The SPECIFIC AIMS are: SA1: To define the synaptic circuitry of hyperactive LHb neurons in animal models of depression. SA2: To determine the synaptic mechanisms underlying aberrant LHb neuronal activity in animal models of depression. SA3: To manipulate the synaptic circuitry of the LHb in order to modulate behavioral depression.) Developing more effective treatments for depression is an important goal. Current antidepressants suffer from critical limitations due to a lack of understanding of the pathophysiology of depression. Results from the proposed research will provide important insights into the cellular and circuit mechanisms of depression that may lead to novel and effective treatments capable of ameliorating some forms of depressive disorders. PUBLIC HEALTH RELEVANCE: The neurobiological mechanisms of depressive disorders remain poorly understood, and the clinical antidepressants are far from being satisfying. In this research program, we propose to determine the role of the lateral habenula, a brain region that was recently suggested to encode disappointment through its modulation of dopamine centers, in the pathogenesis and treatment of behavioral depression in animals. Through this research we will gain novel insights into the neurobiological changes underlying depressive disorders, which may lead to more effective therapeutic treatments.